A large number of drugs, currently in clinical use, are chiral molecules containing one or more asymmetric centers; in many cases these drugs are used as racemic mixtures even if the therapeutic effect is sometimes due to only one of the isomers forming the racemic mixture.
A great attention is recently directed to the role of stereoselectivity principles in the design of biologically active molecules.
Since the stereoselectivity principle is a general rule in biology rather than an exception, often only one of the components of a racemic mixture (the "eutomer") is the active drug while the other one, that is not complementary to the receptor (the "distomer"), is poorly active, or inactive if not even an antagonist.
Except for a few cases when a racemate is more active, less toxic or of longer (or shorter) duration of action then the single components of the racemic mixture, the use of pure enantiomers instead of racemates is today preferred, in order to reduce the xenobiotic load in the living organism, and to avoid risks of toxic side-effects due to the distomer or tis metabolites (see for example E. J. Ariens, "Stereochemistry, a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacology", Eur. J. Clin. Pharmacol., 26, 663, 1984).
The increasing use of "eutomers" in therapy instead of racemates requires, or course, the development of effective, economic and industrially applicable methods of stereoselective synthesis and/or separation and resolution of diastereoisomers and racemates. Optical resolution is often an expensive process and the majority of the methods involves the loss of 50% of the starting racemic material, at least.
The above considerations apply also to the 1,4-dihydropyridine Ca-antagonist family of drugs, that in the last ten years have been introduced in the market for treatment of several cardiovascular diseases, including hypertension, angina of different aetiologies and different types of arrythmias.
The C-4 carbons atom of 1,4-dihydropyridines (see FIG. 1) is a prochiral atom. When at lest one of the substituents, bound to the C.sub.2 and C.sub.3 carbon atoms, is different form those on the symmetric C.sub.6 and C.sub.5 positions of the ring, the C-4 carbon atom is chiral and the compounds are racemates. Nifedipine, (dimethyl, 2,6-dimethyl-4-(2-nitrophenyl) 1,4dihydropyridine-3,5-dicarboxylate) is a symmetrical molecule while many other drugs (for ex. nitrendipine, nimodipine, nisoldipine, nicardipine, niludipine, felodipine, isradipine, ryodipine, Fr 24235, amlodipine and nivaldipine) are chiral 1,4-dihydropyridines that have been used in mammalians and humans as racemates; some of them are already marketed.
Only few dihydropyridines are available for investigation as pure enantiomers, even if it is by now well established that the principles of stereoselectivity apply also to this family of drugs.
Qualitative and quantitative differences between enantiomers of 1,4-dihydropyridines may be shown by "in vitro" studies on tissue preparations or on "in toto" organs (see for example H. Glossmann et al., Arzeneim. Forsch./Drug. Res. 35 (12a), 1917, 1985).
More recently, a report by T. Kazuharu (J. Med. Chem., 29 2504, 1986) point out the importance of stereoselectivity: of the four possible diastereoisomers the S,S enantiomers [(S,S)-YM-09730)] proved to have the greatest potency and the longer duration of action.
The use of enantiomerically pure 1,4-dihydropyridines was recently claims in Ep 0240828 and 0273344.
At present, few and very complex methods are available for preparing enantiomerically pure dihydropyridines.
In absence of basic groups (that could then be salified with optically active acids), the known methods required the selective cleavage of an ester group to form a racemic monocarboxylic acid that is salified with optically pure bases. The mixture of diasteroisomeric salts is separated to recover enantiomerically pure acids that are then esterified with chiral and achiral alcohols to give the desired pure enantiomers. The chiral alcohols used in this esterification process must be pure enantiomers to avoid formation and separation of diasteroisomers. Thus, for instance, the preparation of nicardipine enantiomers (J. Shibanuma et al., Chem. Pharm. Bull., 28, 2809, 1980), involves the synthesis of racemic 1-ethoxy-5-methoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihy dropyridine-3-carboxylic acid, crystallization of diastereoisomeric salts with cinchonine and cinchonidine followed by esterification of the obtained S- and R- carboxylic acids with the appropriate amino-alkanol and final elimination of the N-ethoxymethylene protective group. More recently the same procedure and intermediates were used in the synthesis of four YM-09730 diastereoisomers (T. Kazuharu, above cited).
In both cases the synthesis of the racemic acid involves the use of ethoxy-methylene-chloride, whose mutagenicity is well ascertained.
More recently, to overcome this drawback, mono tert-butyl esters have been introduced as precursors of the carboxy group of racemic 1,4-dihydropyridines; tert-butyl esters may be selectively cleaved by reaction with trialkyl silyl iodides (JP Pat. Appln. 1161-263). The procedure is particularly convenient in the absence of other ether and/or thioether groups that could be simultaneously cleaved, when present. Alterative procedures involve the synthesis of diasteroisomeric mixtures of optically active 1,4-dihydropyridines, wherein one of the carboxy groups is esterified by an optically active alcohol. Since the components of the mixture may be separated by fractional crystallization or by chromatographic techniques the subsequent selective removal of the chiral alcohols yield pure enantiomeric acids that are esterified with an achiral alcohol (E. Winger et al. DE 2935451, 1981). Enantiomeric Ca-agonist or Ca-antagonist 4-aryl-5-nitro-1,4-dihydropyridines were prepared using this procedure (EP 186028); the removal of the optically active 2-methoxy-2-phenylethanol was carried out by selective saponification. To achieve total selectivity during the removal of chiral alcohols (made possible by reductive cleavage with zinc in acetic acid), A. J. G. Baxter et al. (Abst. 310, IX Medicinal Chem. Symp., Berlin, 1986) used (S)-1-phenyl-2-trichloroethanol as an alternative for creating diasteroselectivity; in this way both the enantiomers of FPL 61810XX were prepared; only one of them, the (+enantiomer, showed Ca-antagonist properties. The most evident drawbacks of these methods are:
a) expensive and complex operations during the separation of diastereoisomers; PA0 b) availability of unexpensive enantiomerically pure alcohols, that cannot be recycled when removed by reductive cleavage. PA0 a) salification of the isothioureido moiety with chiral acids; PA0 b) separation of the diastereoisomers isothiouronium salts and their transformation into isothioureido moieties or other isothiouronium salts with achiral acids; PA0 c) optional transformation of the compounds obtain in b) by reactions of desulphuration, hydrolysis, S-acylation, S-alkylation, esterification. PA0 the use of protic solvent helps the exchange reaction between ionic species but it often makes crystallization of diastereoisomeric salts difficult; PA0 in protic and aqueous solvents, an excess of basic slats may cause the base-catalyzed cleavage of isothiouronium salts so as to release thiols and thiourea or salt thereof; PA0 the co-precipitation of salts (originated from the achiral counter-ions) makes the purification of desired diasteroisomeric isothiouronium salts difficult; PA0 increased costs due to the additional process of salification of the resolving chiral acid with a suitable cation with the risk of decreasing the enantiomeric purity of the resolving acids. PA0 R.sub.3 is a free or esterified carboxy group (--CO.sub.2 R.sub.31); PA0 R.sub.4 is a member of selected from the group consisting of: PA0 R.sub.6 is (C.sub.1 -C.sub.6)-alkyl, (C.sub.1 -C.sub.4)-halo-alkyl, --CHO, --C.tbd.N, a carboxyester (--CO.sub.2 R.sub.33), an acetal --CH(OR.sub.61)(OR.sub.62) or a linear or cyclic thioacetal --CH(SR.sub.61)(SR.sub.62): PA0 R.sub.2 is a member selected from the group consisting of: PA0 R.sub.21, R.sub.22 and R.sub.23, are independently selected from hydrogen, (C.sub.1 -C.sub.4)-alkyl, phenyl-(C.sub.1 -C.sub.4)-alkyl or (C.sub.1 -C.sub.4)-acyl, or R.sub.21 and R.sub.22 taken together with the carbon atom to which they are linked to form a group --(CH.sub.2)-.sub.m -- wherein m is an integer 2to 4; PA0 R.sub.24 and R.sub.25 are independently hydrogen, (C.sub.1 -C.sub.4)-alkyl, phenyl(C.sub.1 -C.sub.4)-alkyl, cycano-(C.sub.1 -C.sub.4)-alkyl, (C.sub.1 -C.sub.4)-alkoxycarbonyl-(C.sub.1 -C.sub.4)-alkyl, benzoyl, (C.sub.1 -C.sub.4 -acyl); PA0 R.sub.26 and R.sub.27, that can be the same or different, are a (C.sub.1 -C.sub.6)-alkyl or aryl-(C.sub.1 -C.sub.4)-alkyl group; PA0 R.sub.31 R.sub.32, R.sub.33 and R.sub.34, that may be the same or different, are selected from (C.sub.1 -C.sub.4)-alkyl, (C.sub.1 -C.sub.3)-alkoxy-(C.sub.1 -C.sub.4)-alkyl, (C.sub.2 -C.sub.6)-alkenyl or phenyl-(C.sub.2 -C.sub.6)-alkenyl, mono-, di- or tri-halo-alkyl; PA0 R.sub.51 is a (C.sub.1 -C.sub.4)-alkyl, (C.sub.1 -C.sub.3)-alkoxy-(C.sub.1 -C.sub.4)-alkyl, aryl or aryl-(C.sub.1 -C.sub.4)-alkyl; PA0 R.sub.52 is a (C.sub.1 -C.sub.4)-alkyl or phenyl; PA0 R.sub.61 and R.sub.62 may be (C.sub.1 -C.sub.4)-alkyl or phenyl-(C.sub.1 -C.sub.4)-alkyl, and each of OR.sub.61, OR.sub.62, SR.sub.61 or SR.sub.62, taken together with the carbon atom to which they are linked, form respectively a 1,3-dioxolane or a 1,3-dithiolane ring, which may be optionally substituted by (C.sub.1 -C.sub.3)-alkyl or halo-(C.sub.1 -C.sub.3)-alkyl; PA0 Y.sup.(-) is a monovalent anion selected from chlorine, bromine, iodine and BF.sub.4.sup.- (--); PA0 (C.sub.1 -C.sub.24)acyl is the residue of an aliphatic, aromatic, cycloaliphatic, arylaliphatic, heterocyclic, heteroaliphatic and heteroarylaliphatic carboxylic acid; PA0 n is an integer 1 to 4.
Finally, EP 273349 discloses a resolution process comprising the salification with optically active bases of racemic 1,4-(1H)-dihydropyridines carrying a free carboxy group that were presumably obtained by direct Hantzsch synthesis, whose compatibility with the used reagents and esterification methods has to be clarified.